Patients with cancer commonly develop a wasting syndrome termed the anorexia/cachexia syndrome. It increases in prevalence with advancing disease and occurs in more than 80% of patients with advanced cancer. It is an incompletely understood condition that is believed to have multifactorial causality. There are no strict diagnostic criteria but the condition is commonly recognised to include weight loss, anorexia, fatigue/weakness, chronic nausea, decreased performance status and psychological stress from changes in body image. It is refractory to nutritional intervention. The syndrome results in increased morbidity, and is estimated to account for 10%-20% of cancer deaths. Cancer cachexia involves more than just deficiency of calorie intake.
Weight loss that occurs in cancer patients differs from that in starvation, where there is a preferential loss of bodyweight from fat accounting to 75% of the weight loss, the residual occurring from muscle. This is in contrast to cancer patients where weight loss is due equally to fat and muscle. It is thought that a combination of tumour by-products and host cytokine release that occur in cancer cachexia/anorexia combine to produce metabolic abnormalities. In cancer, TNF, IL1, IL6 and interferon gamma are particularly, though not exclusively thought to be involved. In addition the tumour can produce substances which produce cachexia. Significant muscle mass is lost in cachexia but metabolic changes also occur. These include excess lactate production and preferential atrophy of the type 2 muscle fibres which are responsible for high anaerobic glycolytic metabolism.
Current treatments for cancer cachexia include the use of progestational agents, megestrol acetate and medroxyprogesterone acetate, and corticosteroids including dexamethasone, methylprednisolone and prednisolone. Potential treatments include the use of COX-2 inhibitors, for example celecoxib, nimesulide, ketorolac, indomethacin, ibuprofen, etodolac and diclofenac; cannabinoids for example dronabinol; antidepressants such as mirtazapine and olanzapine; cytokine modulators such as thalidomide; pentoxifylline; metabolic inhibitors such as hydrazine sulphate; anabolic agents such as oxandrolone, nandrolone decanoate and fluoxymesterone; angiotensin converting inhibitors; angiotensin II antagonists; and renin inhibitors.
Megestrol acetate has been most studied in the class of progestational agents (progestins). It has been shown to produce a weight gain of greater than 5% in 15% of cancer patients treated and there is evidence that a significant component of the gain is due to fat. Its mechanism of action is unclear and could be related to anabolic glucocorticoid activity, effects on cytokine release, and inhibition of IL1 and IL6 as well as TNF. It has a stimulatory effect on appetite. In several clinical trials megestrol acetate or medroxy-progesterone acetate (MPA) have been found to improve appetite, calorie intake and nutritional status. Megestrol has demonstrated benefit from doses ranging from 160 mg (40 mg orally four times per day) to 1600 mg on appetite, calorie intake, body weight gain (mainly fat) and sensation of well-being, with an optimal dose of 800 mg/day. It is recommended that a patient be started on the lowest dose (160 mg/day) and the dose be titrated upwards, according to the clinical response.
Adverse effects are related to drug dosage. These effects include, also for medroxyprogesterone acetate, thromboembolism, increased peripheral oedema, hypertension, hyperglycaemia, alopecia, Cushing's syndrome, adrenal suppression, and adrenal insufficiency if they are suddenly discontinued. Progestins are recommended for patients with an expected survival time of greater than 4 weeks.
Corticosteroids have marked symptomatic effects and increase appetite, food intake, sensation of well-being and performance status. This effect is however limited to a few weeks. Due to the significant side effects of long-term treatment and their short duration of action for cachexia, they are more appropriately used in patients with a short expected survival time and where weight gain is not an expected outcome.
In addition to cancer cachexia, a severe loss of muscle mass and strength, often in association with loss of fat mass, is associated with a number of other conditions and diseases including dystrophy, sepsis, AIDS, burn injury, chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF).
It has recently been shown (Busquets et al 2004, Cancer Res 64:6725-6731) that administration of the β2-agonist racemic formoterol to both rats and mice bearing highly cachectic tumors, resulted in a reversal of the muscle-wasting process. The anti-wasting effects of the drug were based on both an activation of the rate of protein synthesis and an inhibition of the rate of muscle proteolysis. Northern blot analysis revealed that formoterol treatment resulted in a decrease in the mRNA content of ubiquitin and proteasome subunits in gastrocnemius muscles; this, together with the decreased proteasome activity observed, suggest that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. Interestingly, formoterol was also able to diminish the increased rate of muscle apoptosis (measured as DNA laddering as well as caspase-3 activity) present in tumor-bearing animals. These authors concluded from their study that formoterol exerted a selective powerful protective action on heart and skeletal muscle by antagonising the enhanced protein degradation that characterises cancer cachexia; in addition, formoterol also had a protective action against the apoptotic effects of skeletal muscle. They also concluded that “conversely to what is found with other β2 agonists that have numerous side effects and considerable toxicity in humans, formoterol could be revealed as a potential therapeutic tool in pathological states wherein muscle protein hypercatabolism is a critical feature, such as cancer cachexia or other wasting diseases.”
Ritodrine is currently used to produce uterine relaxation in pregnant women. As reported in U.S. Pat. No. 5,449,694, (−)-ritodrine is the more potent enantiomer.
Indacaterol, also known as QAB-149 or 5-[(R)-2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one, is an adrenergic β2 agonist. It is a long acting bronchodilator being developed as a potential once daily treatment for asthma and COPD. Administration for these respiratory conditions is conducted using a multidose dry powder inhaler.